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Gallon, L.

Publications and source records attributed to Gallon, L..

2 recordsLinked to original sources

Deep-learning Based Pathological Assessment of Frozen Procurement Kidney Biopsies Predicts Graft Loss and Guides Organ Utilization: A Large-scale Retrospective Study

BackgroundLesion scores on procurement donor biopsies are commonly used to guide organ utilization. However, frozen sections present challenges for histological scoring, leading to inter- and intra-observer variability and inappropriate discard. MethodsWe constructed deep-learning based models to recognize kidney tissue compartments in H&E stained sections from procurement biopsies performed at 583 hospitals nationwide in year 2011-2020. The models were trained and tested respectively on 11473 and 3986 images sliced from 100 slides. We then extracted whole-slide abnormality features from 2431 kidneys, and correlated with pathologists scores and transplant outcomes. Finally, a Kidney Donor Quality Score (KDQS) incorporating digital features and the Kidney Donor Profile Index (KDPI) was derived and used in combination with recipient demographic and peri-transplant characteristics to predict graft loss or assist organ utilization. ResultsOur model accurately identified 96% and 91% of normal/sclerotic glomeruli respectively; 94% of arteries/arterial intimal fibrosis regions; 90% of tubules. Three whole-slide features (Sclerotic Glomeruli%, Arterial Intimal Fibrosis%, and Interstitial Fibrosis%) demonstrated strong correlations with corresponding pathologists scores (n=2431), but had superior associations with post-transplant eGFR (n=2033) and graft loss (n=1560). The combination of KDQS and other factors predicted 1- and 4-year graft loss (discovery: n=520, validation: n=1040). Finally, by matching 398 discarded kidneys due to "biopsy findings" to transplanted population, the matched transplants from discarded KDQS<4 group (110/398, 27.6%) showed similar graft survival rate to unmatched transplanted kidneys (2-, 5-year survival rate: 97%, 86%). KDQS [&ge;] 7 (37/398, 9.3%) and 1-year survival model score [&ge;] 0.55 were determined to identify possible discards (PPV=0.92). ConclusionThis deep-learning based approach provides automatic and reliable pathological assessment of procurement kidney biopsies, which could facilitate graft loss risk stratification and organ utilization. Translational StatementThis deep-learning based approach provides rapid but more objective, sensitive and reliable assessment of deceased-donor kidneys before transplantation, and improves the prognostic value of procurement biopsies, thus could potentially reduce inappropriate discard and stratify patients needing monitoring or preventative measures after transplantation. The pipeline can be integrated into various types of scanners and conveniently generates report after slide scanning. Such report can be used in conjunction with pathologists report or independently for centers lacking renal pathologists.

bioinformatics↗

Multiscale genetic architecture of donor-recipient differences reveals intronic LIMS1 locus mismatches associated with long-term renal transplant survival

BackgroundLong-term kidney allograft survival remains suboptimal. Emerging evidence indicates donor-recipient (D-R) mismatches outside of human leukocyte antigens (HLA) contribute to graft survival but mechanisms remain unclear, specifically for those mismatches within intronic regions. MethodsWe analyzed genome-wide SNP data of D-R pairs from two well-phenotyped kidney transplant cohorts (median follow-up ~1800 days), Genomics of Chronic Allograft Rejection (GoCAR; n=385) and Clinical Trials in Organ Transplantation 1/17 (CTOT1/17; n=146), quantifying genetic mismatches outside of HLA for every D-R pair at variant, gene, and genome-wide scales. ResultsUnbiased genome-wide screen of GoCAR D-R pairs uncovered the LIMS1 locus as the topranked candidate where D-R mismatches associated with death censored graft loss (DCGL). Independent of HLA, a previously unreported relationship between mismatches at a highly linked, intronic haplotype of 30 SNPs was seen as associated with DCGL, with confirmatory association in intra-ancestry D-Rs. Validation testing within the CTOT-01/17 showed similar associations with DCGL. Haplotype D-R mismatches showed a dosage effect, and the introduction of minor alleles in the donor to major allele-carrying recipients showed a greater risk of DCGL. Both the new LIMS1 haplotype and the previously reported LIMS1 SNP rs893403 are expression quantitative trait loci (eQTL) for the gene GCC2 in recipient immune cells, without alterations in GCC2 or LIMS1 coding sequences. Transcriptome enrichment analyses performed on whole blood and within multiple T cell subsets demonstrated significant associations of GCC2 gene, and of either allelic locus, with regulation of TGF-beta-SMAD signaling, implying a role in Treg function and association with rejection. ConclusionsOur analysis unravels intronic non-HLA SNP mismatches within LIMS1 that do not induce protein sequence variation but associate with DCGL. By acting as cis-eQTLs for GCC2 expression, these SNPs modulates TGF-beta signaling and T cell function, associating with immune events and graft outcomes. The findings have clinical implications for risk assessment and individualized therapy in kidney transplant recipients.

genetics↗